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Letters in Drug Design & Discovery, 2013, 10, 11-18

11

Boronic Acid Based Inhibitors of Autotaxin: Understanding their

Biological Role in Terms of Quantitative Structure Activity Relationships
(QSAR)
Sotirios Katsamakas and Dimitra Hadjipavlou-Litina*
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki
54124, Greece
Abstract: Autotaxin (ATX or NPP2) is a newly discovered secreted glycoprotein lyso-phospholipase D (lysoPLD). Its
main role is the lysoPLD activity, which transforms lyso-phosphatidylcholine (LPC) into lyso-phosphatidic acid (LPA).
ATX contributes to tumor progression, inflammation, obesity and diabetes and constitutes a target for drug design.
Various synthetic phospholipid analogues have been explored as ATX inhibitors. However, potent and selective non-lipid
inhibitors of ATX are currently not available. Some new ATX inhibitors have been subjected to a Quantitative-Structure
Activity Relationships (QSAR) analysis. CMR represents the calculated molar refractivity of the molecules and seems to
govern the ATX inhibition. Steric factors are obviously important. No role for lipophilicity was found. Electronic
parameters are not found to be present.

Keywords: Boronic Acid based Autotaxin Inhibitors; Hydrophobicity; Molar Refractivity; QSAR.
INTRODUCTION
Autotaxin (ATX or NPP2) is a newly discovered secreted
glycoprotein lyso-phospholipase D (lysoPLD) [1]. Although
autotaxin has been known for several years as a motility
stimulating factor in melanoma cells, belonging to the ectonucleotide pyrophosphate phosphodiesterase family, its main
role is its lysoPLD activity, which transforms lysophosphatidylcholine (LPC) into lyso-phosphatidic acid
(LPA). LPA is generated by activated platelets and tumor
cells and elicits a wide range of biological effects including
the stimulation of cell proliferation, and migration, as well as
the promotion of cell survival, platelet aggregation,
apoptosis and smooth muscle contraction [2]. LPA acts
through a large spectrum of seven transmembrane domains
and G-protein-coupled receptors [2b, 3]. There are at least
two pathways for LPA production [4]. In serum or plasma,
LPA is predominantly produced by autotaxin (ATX). LPA is
also produced from phosphatidic acid (PA) by its deacylation
catalyzed by phospholipase A (PLA)-type enzymes.ATX is
the major source of LPA, which mediates a broad range of
biological activities through the activation of G protein
coupled cell surface receptors to stimulate events central to
organismal fate, such as wound healing, brain development,
and vascular remodeling [4-5]. Recent studies of ATX
knockout mice suggest that ATX contributes to tumor
progression by stabilizing blood vessels in the vicinity of
tumors [6]. It is also suspected that autotaxin might play a
key role in diabetes/obesity [1a, b, 7]. ATX is an
extracellular prometastatic enzyme and therefore an
attractive molecular target for melanoma because inhibitory
*Author correspondence to this author at the Department of Pharmaceutical
Chemistry, School of Pharmacy, Aristotle University of Thessaloniki,
Thessaloniki 54124, Greece; Tel: +302310997627;
E-mail: hadjipav@pharm.auth.gr
17-;/13 $58.00+.00

compounds can reach the target site without having to

crossthe cell membrane. LPA analogues are effective ATX
inhibitors [8] and successfully inhibit tumor growth in
animal models [9], but LPA mimics could also bind and
activate LPA receptors initiating the signaling cascades that
an ATX inhibitor is intended to stop. Two recent studies
identified several small-molecule ATX inhibitors [8d, 9].
Various synthetic phospholipid analogues have been also
explored as ATX inhibitors [8b, c, 10]. However, lipid based
inhibitors have the disadvantage that they could act as
agonists or antagonists for any of the lysophosphatidic acid
(LPA) and sphingosine 1-phosphate S1P receptors.
The last years an extreme effort has been made from
several researchers in order to develop new ATX inhibitors.
However, potent and selective non-lipid inhibitors of ATX
are currently not available. In the present study some new
ATX inhibitors [11] will be subjected to a QSAR analysis.
QSAR methodology has become increasingly helpful in
understanding many aspects of chemical biological
interactions in drug-design process. QSAR is a useful means
for maximising the potency of a new lead compound. In the
lead optimisation phase of the synthetic project, various
QSAR procedures have been proposed with the aid of
computer technology. Among them, the classical Hansch
approach [12] has been widely used leading to several
successful examples. According to this approach the
interactions of sets of congeners with macromolecules or
macromolecular systems, can be mathematically described in
terms of the physicochemical properties of the small organic
molecules. In the QSAR approaches, the prescription to
optimise the lead structure is inferred from mathematical
equations correlating variations in the congeneric molecules.
The QSAR procedures are based on physical organic
concepts and involve calculational operations.

2013 Bentham Science Publishers

12 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1

Katsamakas and Litina

OH
Bortezomib

F
O

N
H

H
N

OH
B

O
OH

OH

HA155
O

Structure 1a

MATERIAL & METHODS

The data has been collected from the literature
(respective reference is given [11]). In the formulation of the
QSAR we have used only calculated lipophilicity values
(clogP is the calculated n-octanol/water partition coefficient
(P partition constant), using the CLOGP program of Biobyte
[13b]. The used methodology, as well as all parameters, has
been discussed in detail [12c, 14]. The values of substituent
constants molar refractivity, MR have been calculated and
the QSAR regression analyses were executed with the CQSAR program of BioByte[13a]. In QSAR equations, n is
the number of data points, r is the correlation coefficient, r2
is the goodness of fit, Q2 is the goodness of prediction and s
is the standard deviation. The equations were derived
starting from relatively small set of descriptors and this
research deals with relatively small sets of compounds, so
that the choice of linear or nonlinear multivariate regression
analysis is reasonable and the most appropriate. Multivariate
linear regression models were used. This technique is simple
and can produce good models [15].
RESULTS AND DISCUSSION
Huib Ovaa et al. [11] screened small-molecule libraries
to search for unique ATX inhibitors. Among them they
identified thiazolidinedione compounds that selectively
inhibit ATX. In continuation they optimized these molecules
by adopting an active-site-targeted strategy targeting the
catalytic T210 residue in ATX by introducing a boronic acid
moiety. Boronic acid has previously been shown to be
crucial in anticancer therapy. This group has been proved
successful for the development of bortezomib [16] (structure
1a) a boronic acid-based highly selective, reversible inhibitor
of the 26S proteasome inhibitor, which is in clinical use.
This drug is thought to inhibit many proteins (known as
proteasomes) that cancer cells need to survive and multiply.
It has been shown to have anti-tumor activity in B cell
malignancies.
Boronic acid-based small molecules are highly listed as
candidates to target ATX. Studying the crystal structure of
ATX liganded with inhibitor HA155 (structure 1b), Huib
Ovaa and his colleagues suggested that: a) 4-fluorobenzyl
moiety is bound into the hydrophobic lipid binding pocket of
ATX, b) the thiazolidine-2,4-dione core and the conjugated
aromatic ring are located between the hydrophobic pocket
and the catalytic site, and they used these observations for a
rational inhibitor synthetic modification approach.
Molecular docking studies suggested a remarkable
binding pose for one of the synthesized isomers, which

Structure 1b

differs from the original binding pose of inhibitor HA155

(structure 1b).
The synthesized compounds are given in Table 1a [11a].
Among the synthesized derivatives the sulfur atom has been
replaced by nitrogen, amino or methylene moieties (N, NH,
NCH3, or CH2).
IC50 values have been determined in the choline release
assay using 40 M LPC and 10 nM ATX [11a]. We analyzed
these values to receive eq. (1a)
Log1/IC50 = 1.514(0.878)CMR + 2.013(0.705)ID +
25.726(11.085) (eq. 1a)
N =12, r = 0.907, r2 = 0.823, Q2 = 0.714, S = 0.395,
F1,10 = 10.941,
= 0.01, F1,9 = 15.223,
= 0.01, F2,9 =
20.868,
= 0.01
CMR represents the molar refractivity of the molecules.
Its negative sign brings out a steric effect. CMR is the
calculated molar refractivity for the whole molecule. MR is
calculated according to Lorenz-Lorenz equation: (n2- 1/n2 +
2) (MW/d), where n is the refractive index, MW is the
molecular weight and d is the density of a substance. MR
depends on the volume and the polarizability. MR values
have been scaled by 0.1 and can be used for a substituent or
for the whole molecule. The presence of a double bond
seems to be favourable for the inhibitory activity. The
indicator variable I-D applies to the assigned in structure
(Table 1a) double bond.
According to our linear model the molecules do not
appear to reach hydrophobic surface, for clog P, r = 0.299.
No role for lipophilicity in terms of clog P was found for this
type of molecules. Clog P is the calculated partition
coefficient in octanol/water and is a measure of
hydrophobicity. There is no high mutual correlation between
Clog P and MR. Clog P and CMR correspond to the neutral
form of partially ionized compounds.
All terms are orthogonal.
The electronic effect does not seem to influence the
activity, through our analyses. No parameterization has been
done for substituents R and Q. In terms of r2, we found it
necessary to omit two compounds (compounds 6 and 9)
Table 1a. These outliers-compounds are unable to fit in eq.
1a. They present very close experimental IC50 values, while
they contain different structural characteristics e.g. N/S in
the R substitution. Also, in compound 6 one double bond
next to the heteroatom of the ring is missing. Usually,
outliers [17] are valuable in defining the limitations under

Boronic Acid based Autotaxin Inhibitors QSAR

Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1

Table 1a. Structures, biological data and physicochemical parameters used to obtain equation 1a.
OH
B

F
N

Q
S

No.

HN

7.15

6.99

0.16

13.70

8.00

7.70

0.30

13.24

8.08

7.75

0.33

13.20

7.60

6.14

1.46

12.93

5.80

5.96

-0.16

13.05

6.17

6.35

-0.18

12.80

7.58

8.74

-1.16

12.55

8.14

8.60

-0.46

12.64

OH
B
O

OH
OH
B

OH

OH
B

N
H

13.24

OH

OH

-0.87

OH
B

10

7.76

OH

*9

6.83

OH
NH

OH

12.98

OH

O
NH

OH

0.16

*6

B
NH

8.08

OH

8.24

B
OH

ID

Log1/IC50

Log1/
IC50

CMR

Log1/IC50

OH

Calcd

OH

Obsd

OH
B

ID

OH

OH
OH

B
O

OH

13

14 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1

Katsamakas and Litina

Table 1a. Contd.

No.

11

Calcd

ID

Log1/IC50

Log1/
IC50

CMR

Log1/IC50

8.17

8.04

0.13

13.01

8.28

8.04

0.24

13.01

7.26

7.07

0.19

12.32

7.23

7.07

0.16

12.32

Obsd

OH
B

O
N

OH

O
OH

N
12

N
O

OH

O
O
OH

N
13

N
O

OH

O
O
OH

N
14

N
O

OH

*Data omitted from derived equation.

which compounds act by a common molecular mechanism

modeled by one or more physicochemical properties, and
also in defining the experimental limitations of the biological
test data. These outliers may be acting by a different
mechanism or interacting with the enzyme in different
modes.
Modification of eq. 1a leads to eq. 1b. Here, we replaced
CMR and we inserted instead MR as a parameter for
substituents R (MR-R) and Q (MR-Q). (Table 1b)
Log1/IC50 = 1.735(1.386)MR- Q + 1.296(0.985)MR-R +
2.027(0.744)ID + 9.341(5.804) (eq. 1b)
2

N = 13, r = 0.901, r = 0.813, Q = 0.597, S = 0.407, F3,9 =

13.003,  = 0.01
MR-R and MR-Q are a measure of the volume and
polarizability of groups R and Q and they have been used as
an alternative theoretically assessable bulk factor replacing
the overall CMR. The negative sign brings out a steric
problem. There is no high mutual correlation between Clog
P and MR (Clog Pvs MR-R =0.243,Clog Pvs MR-Q
=0.003). Compound 6 is not included in the equation. The
number of data points (12) is small, but the correlation is
significant in terms of r and F. However this QSAR model

does not fulfil the thumb rule condition that is (number of

data points) / (number of descriptors)
5.
Each regression equation includes: 95% confidence
limits for each term in parentheses, the correlation
coefficient r, between observed values of the dependent and
the values calculated from the equation, the s standard
deviation, q2 square of cross-validated correlation coefficient
(a measure of the quality of model, calculated as described
by Cramer et al.) [18], is often computed in order to test the
stability of model and the F-values for the individual term.
The standard deviation s is a measure of how well the
function derived by the QSAR analysis predicts the observed
biological activity. The smaller the value of s, the better is
the QSAR. Fischer statistic (F) is a value derived from F-test
indicating the probability of a true relationship, or the
significance level of the MLR model. The F-value is the
ratio between explained and unexplained variance for a
given number of degree of freedom. The larger the F-value
the greater the probability that the QSAR equation is
significant.
Compounds were assigned to be outliers on the basis of
their deviation between observed and calculated activities
from the equation. Each regression equation includes 95%
confidence limits for each term in parentheses.

Boronic Acid based Autotaxin Inhibitors QSAR

Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1

15

Table 1b. Structures, biological data and physicochemical parameters used to obtain equation 1b.

OH
B

Q
S

No.

O
O

2.84

7.15

6.97

0.18

4.66

2.84

8.00

7.78

0.22

4.19

2.84

8.08

7.84

0.24

4.16

2.84

7.60

6.19

1.48

3.94

2.79

5.80

6.27

-0.47

3.94

2.91

6.17

5.94

0.23

3.94

2.66

7.58

7.64

-0.06

3.94

2.41

8.14

7.77

0.37

3.94

2.50

OH

N
H

4.19

OH

-0.95

OH

10

7.78

OH

N
S

OH
B

2.84

OH

OH

3.94

OH
B

0.03

OH

6.83

ID

OH
B

*6

8.21

MR- R

OH

8.24

MR-Q

OH
B

Log1/IC50

OH

Log1/IC50

OH
B

Log1/IC50

OH

OH
B

Calcd

OH

Obsd

OH
B

ID

OH

OH
OH

B
O

OH

16 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1

Katsamakas and Litina

Table 1b. Contd.

No.

N
11

Obsd

Calcd

Log1/IC50

Log1/IC50

Log1/IC50

8.17

8.24

8.28

MR-Q

MR- R

ID

-0.07

3.94

2.87

8.24

0.04

3.94

2.87

7.26

7.12

0.14

3.94

3.57

7.23

7.12

0.11

3.94

3.57

OH
B

O
N

OH

O
OH

N
12

N
O

OH

O
O
OH

N
13

N
O

OH

O
O
OH

N
14

N
O

OH

O
*Data omitted from derived equation.

CONCLUSION
The QSAR studies reported here derived from our own
research and were not given with the original data set taken
from the literature as referenced [11]. The presented studies
are based on too few compounds that do not yield very good
correlations. Also, due to the limited number, we could not
split the data into a training and a test set. However the
statistics for the equations are good bringing out the fact that
steric factors are significant and must be taken under
consideration in the future design of more potent ATX
inhibitors. It is commonly assumed in QSAR studies that
when CMR/MR appears with negative sign [19], it indicates
steric interactions. Polarizability [19a, 20] has also been
shown to be important indicating that some Van der Waals
type of interaction can also take place between the inhibitors
and the protein. The presence of steric terms suggests that a
protein is involved. Thus, coefficients with steric terms may
reflect the complex process of displacement of the ligand.
The negative steric term (CMR, MR) implies that the critical
effects are occurring on (in) an active site on a
macromolecule.

hydrophobicity did not seem to be an important determinant

of activity from our analysis. The correlation matrix shows
that clog P and CMR' are reasonably independent vectors.
Clog P cannot replace CMR in equation 1a, because
substituting clog P for CMR gives a poor fit which is not
acceptable (r = 0.299). Electronic parameter, are not found to
be present. Thus, hydrogen bonds or other electrostatic
interactions with key amino acids were not delineated
through this analysis.
CONFLICT OF INTEREST
We did not have any financial support and there is no
conflict of interest
ACKNOWLEDGEMENTS
The authors are grateful to Biobyte Corp. and Dr Leo for
their support and free access to the C-QSAR program. This
research has been done using the above program via Internet.

Obviously in ATX inhibition, steric factors are important.

From these results it would appear that the bulkiness of the
inhibitor near the zinc binding site is tolerated. The
compounds are incorporated into the active site pocket of the
ATX but require a specific length to fit in the pocket. This
length-bulk must be taken under consideration and must lead
to new ATX inhibitors.

DISCLOSURE

Parabolic correlations with CMR were not found.

Although the researchers [11] pointed to a lipophilic effect,

[1]

Part of information included in this article has been

previously published in Medicinal Research Reviews
Volume 32, Issue 1, pages 1165, January 2012.
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18 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1

[20]

Katsamakas and Litina

Chemical Reviews 2005, 105(9), 3235-3271; (c) Verma, R. P.,

Anti-cancer activities of 1,4-naphthoquinones: a QSAR study.
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Received: June 07, 2012

Sciences 2003, 43(5), 1647-1651; (b) Verma, R. P.; Kurup, A.;

Hansch, C., On the role of polarizability in QSAR. Bioorganic &
Medicinal Chemistry 2005, 13(1), 237-255.

Revised: September 19, 2012

Accepted: September 27, 2012